864754-21-2Relevant articles and documents
Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach
Charoensutthivarakul, Sitthivut,Thomas, Sherine E.,Curran, Amy,Brown, Karen P.,Belardinelli, Juan M.,Whitehouse, Andrew J.,Acebrón-García-de-Eulate, Marta,Sangan, Jaspar,Gramani, Subramanian G.,Jackson, Mary,Mendes, Vitor,Floto, R. Andres,Blundell, Tom L.,Coyne, Anthony G.,Abell, Chris
, p. 296 - 309 (2022/01/28)
Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives
Westaway, Susan M.,Preston, Alex G. S.,Barker, Michael D.,Brown, Fiona,Brown, Jack A.,Campbell, Matthew,Chung, Chun-Wa,Drewes, Gerard,Eagle, Robert,Garton, Neil,Gordon, Laurie,Haslam, Carl,Hayhow, Thomas G.,Humphreys, Philip G.,Joberty, Gerard,Katso, Roy,Kruidenier, Laurens,Leveridge, Melanie,Pemberton, Michelle,Rioja, Inma,Seal, Gail A.,Shipley, Tracy,Singh, Onkar,Suckling, Colin J.,Taylor, Joanna,Thomas, Pamela,Wilson, David M.,Lee, Kevin,Prinjha, Rab K.
, p. 1370 - 1387 (2016/03/05)
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
5, 7-SUBSTITUTED-IMIDAZO [1, 2-C] PYRIMIDINES AS INHIBITORS OF JAK KINASES
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Page/Page column 82, (2011/11/01)
Compounds of Formula I: (Formula should be inserted here) and stereoisomers and pharmaceutically acceptable salts and solvates thereof in which R1, R2, R3, R4, R5, R6, R7, X1 and X2 have the meanings given in the specification, are inhibitors of one or more JAK kinases and are useful in the treatment of autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.
